CSF Findings in Acute NMDAR and LGI1 Antibody–Associated Autoimmune Encephalitis

Abstract

Background and ObjectivesCSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting.MethodsEighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively.ResultsCSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher.DiscussionNMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.

Clinical Features, Treatment, and Prognostic Factors in Neuronal Surface Antibody-Mediated Severe Autoimmune Encephalitis

“…Inflammatory changes in the CSF were noted in 30 (50%) of the patients. We found that patients in the NMDAR-AE and GABAbR-AE groups were more likely to develop CSF pleocytosis than the other subtypes of the cohort; this result is similar to those of other studies (20,21). Previous studies have found an association between CSF changes and worse outcomes (22).…”

NMDAR autoantibodies in psychiatric disease - An immunopsychiatric continuum and potential predisposition for disease pathogenesis

“…However, the pure manifestation of psychiatric symptoms in NMDARE seems to be rare, as shown in a recent investigation by Kayser et al [ 3 ]. NMDARE is often characterized by severe inflammation in the central nervous system (CNS) when compared to other types of membrane-surface autoantibody-related encephalitis types such as LGI1 encephalitis proven by frequent CSF abnormalities [ 26 ] such as pleocytosis [ 27 ]. Furthermore, oligoclonal bands (OCBs) are often found accompanying a severe functional impairment in NMDARE [ 26 ].…”

“…NMDARE is often characterized by severe inflammation in the central nervous system (CNS) when compared to other types of membrane-surface autoantibody-related encephalitis types such as LGI1 encephalitis proven by frequent CSF abnormalities [ 26 ] such as pleocytosis [ 27 ]. Furthermore, oligoclonal bands (OCBs) are often found accompanying a severe functional impairment in NMDARE [ 26 ]. Thus, NMDARE is a prototype of a relative extended neuroinflammation unlike other types of autoimmune encephalitis such as glycine or LGI1 associated encephalitis as shown in a recent CSF study from Blinder and Lewerenz [ 28 ].…”

The serum metabolomic profile of a distinct, inflammatory subtype of acute psychosis

“…However, in spite of the accepted pathogenicity of these antibodies it has also been recognized, paradoxically, that classical measures of neuroinflammation may also be absent in these patients, whether in MRI scans, or in serum or CSF measures of inflammation [ 49 , 50 ]. The absence of a distinctive metabolomic profile in those with NMDAR/LGI1/CASPR2 serum antibodies in psychosis does not necessarily indicate that these antibodies are not having an effect in the brain in these patients.…”